PT - JOURNAL ARTICLE AU - Tarcha, Eric J. AU - Chi, Victor AU - Muñoz-Elías, Ernesto J. AU - Bailey, David AU - Londono, Luz M. AU - Upadhyay, Sanjeev K. AU - Norton, Kayla AU - Banks, Amy AU - Tjong, Indra AU - Nguyen, Hai AU - Hu, Xueyou AU - Ruppert, Greg W. AU - Boley, Scott E. AU - Slauter, Richard AU - Sams, James AU - Knapp, Brian AU - Kentala, Dustin AU - Hansen, Zachary AU - Pennington, Michael W. AU - Beeton, Christine AU - Chandy, K. George AU - Iadonato, Shawn P. TI - Durable Pharmacological Responses from the Peptide ShK-186, a Specific Kv1.3 Channel Inhibitor That Suppresses T Cell Mediators of Autoimmune Disease AID - 10.1124/jpet.112.191890 DP - 2012 Sep 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 642--653 VI - 342 IP - 3 4099 - http://jpet.aspetjournals.org/content/342/3/642.short 4100 - http://jpet.aspetjournals.org/content/342/3/642.full SO - J Pharmacol Exp Ther2012 Sep 01; 342 AB - The Kv1.3 channel is a recognized target for pharmaceutical development to treat autoimmune diseases and organ rejection. ShK-186, a specific peptide inhibitor of Kv1.3, has shown promise in animal models of multiple sclerosis and rheumatoid arthritis. Here, we describe the pharmacokinetic-pharmacodynamic relationship for ShK-186 in rats and monkeys. The pharmacokinetic profile of ShK-186 was evaluated with a validated high-performance liquid chromatography-tandem mass spectrometry method to measure the peptide's concentration in plasma. These results were compared with single-photon emission computed tomography/computed tomography data collected with an 111In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugate of ShK-186 to assess whole-blood pharmacokinetic parameters as well as the peptide's absorption, distribution, and excretion. Analysis of these data support a model wherein ShK-186 is absorbed slowly from the injection site, resulting in blood concentrations above the Kv1.3 channel-blocking IC50 value for up to 7 days in monkeys. Pharmacodynamic studies on human peripheral blood mononuclear cells showed that brief exposure to ShK-186 resulted in sustained suppression of cytokine responses and may contribute to prolonged drug effects. In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis, and pristane-induced arthritis rat models, a single dose of ShK-186 every 2 to 5 days was as effective as daily administration. ShK-186's slow distribution from the injection site and its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease.